DESCRIPTION: (Taken from the application): Once-daily PTH injections increase bone mass and strength more than other treatments in osteoporotic women and men, but rarely cure osteoporosis. Daily PTH injections increase bone resorption as well as formation, so combining them with an anti-resorptive agent should enhance the effect on bone mass. Experiments elsewhere in animals and humans failed to confirm this expectation, but their design made interpretation difficult, so we are treating osteoporotic women and men with PTH, alendronate, or both, serially assessing bone formation and resorption and BMD of multiple sites. This also tests whether PTH must increase bone resorption in order to increase bone formation and BMD in humans, or whether a bisphosphonate interferes with PTH-mediated increases in bone formation. At the end of this experiment we will evaluate skeletal and renal responses to sc PTH, and to a 12-hour iv PTH infusion, stop PTH but not alendronate, follow the patients for a year, and then re-evaluate BMD and acute responses to sc and iv PTH. This will test whether acute renal and early skeletal responses to PTH are restored by a 12 month interval without PTH administration, and whether BMD increases after stopping PTH (because bone remodeling decreases) or whether (as in animals) BMD decreases rapidly after stopping PTH, unless an anti-resorptive agent is administered. We will then treat every patient with PTH for a year (not changing any alendronate treatment), to test whether daily sc PTH's effects on bone turnover are restored by a 12 month interval without PTH administration, with additional increases in BMD. In osteoporotic animals and humans, PTH?s therapeutic effects are limited by a PTH resistance that slowly develops during prolonged daily PTH administration. We will test whether this PTH resistance reflects decreased blood levels of the injected peptide, delayed development of anti-PTH antibodies, down-regulation of PTH-receptors and receptor-mediated activation of adenylate cyclase (in an accessible PTH target organ, the kidney), or a decrease in PTH?s early effects on bone formation (the suppression of bone formation and stimulation of bone resorption seen during a 12-hour intravenous PTH infusion). Finally, we will test in a new set of patients whether PTH resistance can be overcome by serial increases in the administered PTH dose.